A healthy adult pancreas is usually a developmentally stable organ, but a targeted cell loss or aberrant cell growth and development have pathological consequences. For example, in human Insulin Dependent Diabetes Mellitus (IDDM), autoimmune mechanisms cause the selective and permanent destruction of the insulin-producing beta cells in the islets of Langerhans. The lost cells are not restored in vivo, although Sarvetnick et al. Cell 52:773-782 (1988) have shown that beta cells have the potential to regenerate. On the other hand, the proliferation of duct cells can contribute to pancreatic disease pathologies, such as chronic pancreatitis, pancreatic cancer, and cystic fibrosis. Pancreatic duct cell proliferation and differentiation have also been shown by Arnush et al., Lab Invest 74: 985-990 (1995) to play a critical role in a transgenic mouse model of islet regeneration. Further, endocrine cell differentiation is frequently seen in pancreatic duct cell carcinomas, suggesting that duct cell proliferation can lead to islet neogenesis.
Growth factors are critical for modulating cellular proliferation and differentiation. The growth factors that regulate and promote pancreatic growth are not well characterized, but keratinocyte growth factor (KGF), a member of the fibroblast growth factor family, is known to be involved in wound healing and in the differentiation of many epithelial tissues. KGF upregulates epithelial cell proliferation and pancreatic duct cell proliferation in rats. Also, epidermal growth factor (EGF) and transforming growth factor beta-1 (TGF.beta.-1) can induce ductal and endocrine cell development, respectively. EGF, which is known to stimulate epithelial cell and fibroblast proliferation, also has mitogenic properties for pancreatic growth. The overexpression of EGF and EGF receptor (EGF-R) is linked both to chronic pancreatitis and to malignant pancreatic growth.
Yi et al. (Am J Pathol 145: 80-85, 1994) have shown that systemic administration of KGF to rats induces pancreatic duct cell proliferation. KGF stimulated the proliferation of pancreatic ductal epithelial cells in rats after daily systemic injection for 1-2 weeks. Duct cell proliferation was predominantly adjacent to or within the islets of Langerhans and occurred in the absence of physical injury to the pancreas. However, knockout mice lacking KGF do not display significant developmental abnormalities, and pancreatic and liver development appear entirely normal (Guo et al., EMBO J 12: 973-986, 1993).
Clearly, KGF can in some way influence pancreatic growth, and further studies designed to investigate its role in this process would be of considerable value. It is therefore important to expand our knowledge of these growth factors by providing animal models allowing the study of liver and pancreatic growth and development, and associated disease states.